RESUMO

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.

RESUMO

BACKGROUND: Congenital heart disease (CHD) is the most common birth defect and a major health problem around the world. However, its exact etiology has remained unclear. Among various genetic contributing factors, GATA4 transcription factor plays a significant role in the CHD pathogenesis. In this study, GATA4 coding sequence was screened in Iranian patients of various ethnicities. METHODS: Sixty six individuals with familial CHD referred to our center were recruited in this study. After receiving written informed consent from each individual or their parents, chromosomal analyses and GATA4 variant screening were performed. Pathogenicity of the suspected variants was evaluated using available online software tools: CADD, Mutation Taster, SIFT, and PolyPhen-2. RESULTS: A total of twelve GATA4 variants were detected including five intronic, 2 exonic and 3 polymorphisms as well as 2 missense mutations, the c.1220C>A and c.1309G>A. Unlike the c.1220C>A, the likely pathogenic heterozygous c.1309G>A has not been previously associated with any phenotype. Here, we not only report, for the first time, a c.1309G>A-related CHD, but also report a novel de novo balanced translocation, 46,XY,t(5;7)(qter13;qter11), in the same patient which may have influenced the disease severity. CONCLUSION: From screening GATA4 sequence in 66 Iranian patients of various ethnicities, we conclude that cytogenetic analysis and PCR-direct sequencing of different candidate genes may not be the best approach for genetic diagnosis in CHD. Applying novel approaches such as next-generation sequencing (NGS) may provide a better understating of genetic contributing factors in CHD patients for whom conventional methods could not reveal any genetic causative factor.

RESUMO

BACKGROUND: Nowadays, according to valuable resources of high-quality genome sequences, reference-based assembly methods with high accuracy and efficiency are strongly required. Many different algorithms have been designed for mapping reads onto a genome sequence which try to enhance the accuracy of reconstructed genomes. In this problem, one of the challenges occurs when some reads are aligned to multiple locations due to repetitive regions in the genomes. RESULTS: In this paper, our goal is to decrease the error rate of rebuilt genomes by resolving multi-mapping reads. To achieve this purpose, we reduce the search space for the reads which can be aligned against the genome with mismatches, insertions or deletions to decrease the probability of incorrect read mapping. We propose a pipeline divided to three steps: ExactMapping, InExactMapping, and MergingContigs, where exact and inexact reads are aligned in two separate phases. We test our pipeline on some simulated and real data sets by applying some read mappers. The results show that the two-step mapping of reads onto the contigs generated by a mapper such as Bowtie2, BWA and Yara is effective in improving the contigs in terms of error rate. CONCLUSIONS: Assessment results of our pipeline suggest that reducing the error rate of read mapping, not only can improve the genomes reconstructed by reference-based assembly in a reasonable running time, but can also have an impact on improving the genomes generated by de novo assembly. In fact, our pipeline produces genomes comparable to those of a multi-mapping reads resolution tool, namely MMR by decreasing the number of multi-mapping reads. Consequently, we introduce EIM as a post-processing step to genomes reconstructed by mappers.

RESUMO

Genetic contributing factors to non-syndromic hearing loss (NSHL) are remarkably diverse spanning over autosomal to X-linked to mitochondrial inheritance patterns. Facing a quite unconventional pedigree, here we report implementation of whole exome sequencing (WES) to uncover mitochondrial pathogenic variant in a six-generation Iranian family with four cases affected with hereditary NSHL of variable severity. As a result, heteroplasmic transition of A to G at position 1555 of MT-RNR1 gene was identified in all affected individuals co-existing with nuclear c.28Gâ¯>â¯T (p.A10S) variant in the TRMU gene, only in some patients. The reliability of WES to infer nuclear as well as mitochondrial variants in hearing loss were discussed.

RESUMO

BACKGROUND: Trisomy 22 mosaicism is a rare autosomal anomaly with survival compatibility. Recognition of the complete trisomy 22 which is incompatible with life from the mosaic form is critical for genetic counseling. Affected mosaic cases have prevalent clinical presentations such as webbed neck, developmental delay, abnormal ears, cardiac disorders, and microcephaly. Phenotype of these patients is milder than full chromosomal aneuploidy, and the severity of the phenotype depends on the count of trisomic cells. We describe a 4-year-old boy with mosaic trisomy 22 from healthy parents and no family history of any genetic disorders in the pedigree. METHOD AND RESULTS: The patient had determined dysmorphic clinical features including facial asymmetry, cleft palate, gastroenteritis, hydronephrosis, developmental delay, genital anomalies, dysplastic toenails, flattened nasal bridge, congenital heart defect, hearing loss, cryptorchidism, and hypotonic muscle. He is the first reported with hypothyroidism and larynx wall thickness in worldwide and the first with atrial septal defect (ASD) from Iran. Chromosomal analyses using G-banding indicated a de novo Mos 47,XY,+22(6)/46,XY(44) karyotype with no other chromosomal structural changes. CONCLUSIONS: Our observations confirm the importance of cytogenetic analyses for determining the cause of congenital anomalies and provide a useful genetic counseling. In addition, due to the fact that some of mosaic trisomy 22 features are unavoidable such as CHD and general hypotrophy, we suggest including echocardiography test for early diagnosis during the clinical assessment.

RESUMO

The draft genome sequence of Pseudomonas gingeri LMG 5327 (NCPPB 3146), the causative agent of ginger blotch in Agaricus bisporus, is reported. Together with another mushroom pathogen, Pseudomonas agarici, it belongs to a distinct phylogenomic group.

RESUMO

Hypomorphic IKBKG mutations in males are typically associated with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Some mutations cause immunodeficiency without EDA (NEMO-ID). The immunological profile associated with these NEMO-ID variants is not fully documented. We present a 2-year-old patient with suspected immunodeficiency in which a hemizygous p.Glu57Lys IKBKG variant was identified. At the age of 1 year, he had an episode of otitis media that evolved into a bilateral mastoiditis (Pseudomonas spp). Hypogammaglobulinemia, specific (polysaccharide) antibody deficiency, and low switched memory B cell subsets were noticed. The mother was heterozygous for the variant but had no signs of incontinentia pigmenti. Patient peripheral blood mononuclear cells produced low amounts of IL-6 after stimulation with IL-1ß, Pam3CSK4, and FSL-1. In patient fibroblasts, IκB-α was degraded normally upon stimulation with IL-1ß or TNF-α. Transduction of wild-type and variant NEMO in NEMO-/- deficient SV40 fibroblasts revealed a slight but significant reduction of IL-6 production upon stimulation with IL-1ß and TNF-α. In conclusion, we demonstrated that p.Glu57Lys leads to specific immunological defects in vitro. No other pathogenic PID variants were identified through whole exome sequencing. As rare polymorphisms have been described in IKBKG and polygenic inheritance remains an option in the presented case, this study emphasizes the need for thorough functional and genetic evaluation when encountering and interpreting suspected disease-causing NEMO-ID variants.

RESUMO

ZAP-70 deficiency is a rare autosomal recessive form of combined immunodeficiency (CID) characterized by selective absence of circulating CD8 T cells with low, normal, or increased CD4 T cells in peripheral blood. Up to now, 14 unique mutations in the ZAP70 gene have been identified in patients with ZAP-70-related CID. We present a 3-year-old boy with a history of recurrent bacterial infections and autoimmunity. Initial laboratory findings showed a normal total lymphocyte count, but low levels of CD8 and CD4 T cells and an abnormal lymphocyte proliferation response. Immunoglobulin levels were normal, but the specific antibody response was impaired. Whole exome sequencing revealed a mutation within the kinase domain of ZAP-70. ZAP-70 deficiency should be considered in infants and young children with recurrent bacterial infections, in spite of having palpable lymph nodes, a notable thymus shadow, and a normal total lymphocyte count.

RESUMO

Kocuria rhizophila RF, a soil isolate from Iran, is a radiation-resistant bacterium. Only a limited amount of genomic information for radiation-resistant bacteria is currently available. Here, we report the draft genome sequence of this bacterium, providing knowledge to aid in the discovery of the genomic basis of its resistance to radiation.

RESUMO

Gene co-expression analysis is one of the main aspects of systems biology that uses high-throughput gene expression data. In the present study we applied cross-species co-expressional analysis on a module of biofilm and stress response associated genes. We addressed different kinds of stresses in three most intensively studied members of Gammaproteobacteria including Escherichia coli K12, Pseudomonas aeruginosa PAO1 and Salmonella enterica for which large sets of gene expression data are available. Our aim was to evaluate the presence of common stress response strategies adopted by these microorganisms that may be assigned to the other members of Gammaproteobacteria. Results of functional annotation analysis revealed distinct categories among co-expressed genes, most of which concerned biological processes associated with virulence and stress response. Transcriptional regulatory analysis of genes present in co-expressed modules showed that the global stress sigma factor, RpoS, besides several local transcription factors accounts for the observed co-expressional response, and that several cases of feed-forward loops exist between global regulators, local transcription factors and their targets. Our results lend partial support to our underlying assumption of the conservation of core biological processes and regulatory interactions among these related Gammaproteobacteria members. This has led to the implementation of transferring gene function annotations from well-studied Gammaproteobacterial species to less-characterized members. These findings can shed light on the discovery of new drug targets capable of controlling severe infections caused by these groups of bacteria.

RESUMO

The viscosin group covers a series of cyclic lipodepsipeptides (CLPs) produced by Pseudomonas bacteria, with a range of biological functions and antimicrobial activities. Their oligopeptide moieties are composed of both L- and D-amino acids. Remarkably, the Leu5 amino acid-centrally located in the nonapeptide sequence-is the sole residue found to possess either an L or D configuration, depending on the producing strain. The impact of this D/L switch on the solution conformation was investigated by NMR-restrained molecular modelling of the epimers pseudodesmin A and viscosinamide A. Although the backbone fold remained unaffected, the D/L switch adjusted the segregation between hydrophobic and hydrophilic residues, and thus the amphipathicity. It also influenced the self-assembly capacity in organic solvents. Additionally, several new minor variants of viscosinamide A from Pseudomonas fluorescens DR54 were identified, and an NMR assay is proposed to assess the presence of either an L- or D-Leu5.

RESUMO

The interaction of WLIP (white line-inducing principle), a member of the viscosin group of Pseudomonas lipopeptides, with tolaasin, a lipopeptide mycotoxin secreted by Pseudomonas tolaasii, enables identification of the mushroom pathogen relying on formation of a lipopeptide coprecipitate between confronted colonies of an indicator strain (designated Pseudomonas 'reactans') and P. tolaasii. The WLIP non-ribosomal lipopeptide synthesis system of the mushroom isolate P. 'reactans' LMG 5329 (Wip) was identified and shown to be most similar to the Pseudomonas fluorescens SBW25 viscosin system (Visc), but remarkably different from the WLIP-generating Wlp system previously identified in the rice rhizosphere isolate Pseudomonas putida RW10S2. The Wlp machinery is composed of modules most similar to those recruited for biosynthesis of the non-viscosin-type lipopeptides putisolvin and entolysin by strains from the P. putida clade. In line with the pronounced synteny between the wip and visc flanking regions, strain LMG 5329 was identified as an authentic P. fluorescens closely related to strain SBW25. In both P. putida and P. fluorescens, WLIP production confers similar phenotypes of microbial antagonism and surface colonization. Genotypes other than wlp or wip were not identified among WLIP producers isolated from mushroom, maize rhizosphere or water.

RESUMO

The rhizosphere isolate Pseudomonas putida BW11M1 produces a mixture of cyclic lipopeptide congeners, designated xantholysins. Properties of the major compound xantholysin A, shared with several other Pseudomonas lipopeptides, include antifungal activity and toxicity to Gram-positive bacteria, a supportive role in biofilm formation, and facilitation of surface colonization through swarming. Atypical is the lipopeptide's capacity to inhibit some Gram-negative bacteria, including several xanthomonads. The lipotetradecadepsipeptides are assembled by XtlA, XtlB and XtlC, three co-linearly operating non-ribosomal peptide synthetases (NRPSs) displaying similarity in modular architecture with the entolysin-producing enzymes of the entomopathogenic Pseudomonas entomophila L48. A shifted serine-incorporating unit in the eight-module enzyme XtlB elongating the central peptide moiety not only generates an amino acid sequence differing at several equivalent positions from entolysin, but also directs xantholysin's macrocyclization into an octacyclic structure, distinct from the pentacyclic closure in entolysin. Relaxed fatty acid specificity during lipoinitiation by XtlA (acylation with 3-hydroxydodec-5-enoate instead of 3-hydroxydecanoate) and for incorporation of the ultimate amino acid by XtlC (valine instead of isoleucine) account for the production of the minor structural variants xantholysin C and B, respectively. Remarkably, the genetic backbones of the xantholysin and entolysin NRPS systems also bear pronounced phylogenetic similarity to those of the P. putida strains PCL1445 and RW10S2, albeit generating the seemingly structurally unrelated cyclic lipopeptides putisolvin (undecapeptide containing a cyclotetrapeptide) and WLIP (nonapeptide containing a cycloheptapeptide), respectively. This similarity includes the linked genes encoding the cognate LuxR-family regulator and tripartite export system components in addition to individual modules of the NRPS enzymes, and probably reflects a common evolutionary origin. Phylogenetic scrutiny of the modules used for selective amino acid activation by these synthetases indicates that bacteria such as pseudomonads recruit and reshuffle individual biosynthetic units and blocks thereof to engineer reorganized or novel NRPS assembly lines for diversified synthesis of lipopeptides.

RESUMO

The secondary metabolite mediating the GacS-dependent growth-inhibitory effect exerted by the rice rhizosphere isolate Pseudomonas putida RW10S2 on phytopathogenic Xanthomonas species was identified as white-line-inducing principle (WLIP), a member of the viscosin group of cyclic lipononadepsipeptides. WLIP producers are commonly referred to by the taxonomically invalid name "Pseudomonas reactans," based on their capacity to reveal the presence of a nearby colony of Pseudomonas tolaasii by inducing the formation of a visible precipitate ("white line") in agar medium between both colonies. This phenomenon is attributed to the interaction of WLIP with a cyclic lipopeptide of a distinct structural group, the fungitoxic tolaasin, and has found application as a diagnostic tool to identify tolaasin-producing bacteria pathogenic to mushrooms. The genes encoding the WLIP nonribosomal peptide synthetases WlpA, WlpB, and WlpC were identified in two separate genomic clusters (wlpR-wlpA and wlpBC) with an operon organization similar to that of the viscosin, massetolide, and entolysin biosynthetic systems. Expression of wlpR is dependent on gacS, and the encoded regulator of the LuxR family (WlpR) activates transcription of the biosynthetic genes and the linked export genes, which is not controlled by the RW10S2 quorum-sensing system PmrR/PmrI. In addition to linking the known phenotypes of white line production and hemolytic activity of a WLIP producer with WLIP biosynthesis, additional properties of ecological relevance conferred by WLIP production were identified, namely, antagonism against Xanthomonas and involvement in swarming and biofilm formation.

RESUMO

Bacterial lipopeptides (LPs) are a diverse group of secondary metabolites synthesized through one or more non-ribosomal peptide synthetases (NRPSs). In certain genera, such as Pseudomonas and Bacillus, these enzyme systems are often involved in synthesizing biosurfactants or antimicrobial compounds. Several different types of LPs have been reported for non-pathogenic plant-associated Pseudomonas. Focusing on this group of bacteria, we devised and validated a PCR method to detect novel LP-synthesizing NRPS genes by targeting their lipoinitiation and tandem thioesterase domains, thus avoiding amplification of genes for non-LP metabolites, such as the pyoverdine siderophores present in all fluorescent Pseudomonas. This approach enabled detection of as yet unknown NRPS genes in strains producing viscosin, viscosinamide, WLIP, or lokisin. Furthermore, it proved valuable to identify novel candidate LP producers among Pseudomonas rhizosphere isolates. By phylogenetic analysis of these amplicons, several of the corresponding NRPS genes can be tentatively assigned to the viscosin, amphisin, or entolysin biosynthetic groups, while some others may represent novel NRPS systems.

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